A Phase I/II Study of Gene-modified WT1 TCR Therapy in MDS & AML Patients

NCT02550535 | Completed Phase 1 DMC

• 1 other identifier: D-00272-CT2014002
• Study Type: interventional
• Target: 3
• Locations: 3 countries
• Sites: 6

Brief Summary

This is a Phase I/II trial to determine safety, clinical efficacy and feasibility of a gene-modified WT1 TCR therapy in patients with myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). Patient's white blood cells (T cells) will be modified by transferring a gene which enables them to make a new T cell receptor (TCR) that can recognize fragments of a protein called WT1 (Wilms' tumour 1) which is present at abnormally high levels on the surface of myelodysplastic and leukaemic cells. In this trial, approximately 25 participants with an Human Leukocyte Antigen A2 (HLA-A\*0201) tissue type who have failed to achieve or maintain an IWG defined response following hypomethylating agent therapy will be recruited.

Conditions

Myelodysplastic Syndromes (MDS); Acute Myeloid Leukaemia (AML)

Keywords

Gene Therapy; WT1 TCR; Gene modified T cels

Outcome Measures

Primary Outcomes (2)

• Safety following gene-modified WT1 TCR T cell therapy as measured by suspected unexpected serious adverse reactions (SUSARS)

  12 Months

• Proportion of subjects achieving one or more IWG response criteria following gene-modified WT1 TCR T cell therapy

  12 Months

Secondary Outcomes (6)

• Safety and tolerability of gene-modified WT1 TCR therapy as measured by clinical laboratory parameters and adverse events

  12 Months

• Efficacy of WT1 TCR therapy as measured by haematological improvement, overall remission rate, marrow remission, cytogenetic response, molecular response, stable disease, AML transformation, progression free, event free and overall survival

  12 Months

• Technical feasibility of gene-modified WT1 TCR therapy in subjects with Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukaemia (AML).

  12 Months

• Persistence of WT1 TCR-transduced T cells

  12 Months

• Functionality and phenotype of WT1 TCR-transduced T cells

  12 Months

Study Arms (1)

Gene-modified WT1 TCR-transduced T cells

EXPERIMENTAL

A single dose of bulk WT1 TCR-transduced T cells (≤ 2 x 107/kg) will be intravenously (i.v.) administered following protocol-specified lymphodepletive conditioning regimen. Additionally, daily IL-2 subcutaneous injections (1x106 units/m2 subcutaneously (s.c.)) will be administered for 5 days concomitantly to each subject, following infusion of the ATIMP.

Genetic: Autologous WT1 TCR transduced T cells

Interventions

Autologous WT1 TCR transduced T cells GENETIC

Gene therapy: Autologous WT1 TCR transduced T cells administered by intravenous infusion

Gene-modified WT1 TCR-transduced T cells

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• The trial will recruit subjects with MDS or AML who have received hypomethylating agent therapy (at least 6 cycles of azacitidine or 4 cycles of decitabine), and are EITHER:
• Relapsed, defined as failing to maintain an initial IWG response
• Stable, defined as failing to achieve an IWG response
• Subjects who have received hypomethylating agent therapy as part of a combination regimen may be eligible after discussion with the Sponsor.
• Subjects aged 18 years or older who have a diagnosis of, EITHER:
• MDS with an IPSS of intermediate -2, or high and one of the following FAB types:
• Refractory anaemia with excess blasts (RAEB)
• Chronic myelomonocytic leukaemia (CMML) with at least 10% bone marrow blasts (WHO CMML II) OR
• AML (diagnosed according to WHO classification 2008 revision)
• Subjects with documented HLA-A\*0201 positive serotype
• Subjects with less than 30 per cent bone marrow blasts
• Subjects with relapsed disease must have less than 5 per cent peripheral blasts
• Subjects with stable disease must have less than 10 per cent peripheral blasts
• Subjects with less than a doubling of bone marrow blast count between the start of hypomethylating agent therapy and the date of screening
• Subjects to complete screen 1 visit within a minimum of 28 days and maximum of 90 days since completion of azacitidine or decitabine therapy. Subjects who have exceeded the 90 day window may be eligible after discussion with the Sponsor.

You may not qualify if:

• improvement or molecular response following azacitidine treatment
• CMML patients who have a white blood cell count \> 13 x 109/L
• Acute promyelocytic leukaemia (FAB M3 Classification)
• Uncontrolled intercurrent illness
• Active malignancy, except basal cell or squamous cell skin cancer or carcinoma in situ of the cervix or breast
• Known history of Human Immunodeficiency Virus (HIV), Hepatitis C virus (HCV) or Hepatitis B virus (HBV) or positive for Human T-Lymphocyte Virus (HTLV) or Syphilis. • Active auto-immune disease
• Clinically significant non-hematologic toxicity after prior therapy chemotherapy higher than grade 1 per Common Terminology Criteria for Adverse Events (CTCAE) (v 4.0)
• Subjects who require haemodialysis or peritoneal dialysis
• Pregnant and lactating women
• Subjects unwilling or unable to use adequate contraceptive precautions at screening and throughout the trial
• Subjects who have undergone major surgery without full recovery within last 28 days prior to screening
• Subjects with known hypersensitivity to cyclophosphamide, fludarabine, methylprednisolone or IL-2 (Interleukin-2)

Sponsors & Collaborators

• Cell Medica Ltd: lead
• University College, London: collaborator
• Cell Therapy Catapult: collaborator

Study Sites (6)

AZ St Jan Brugge-Oostende AV

Bruges, B-8000, Belgium

Location

UZ Leuven

Leuven, B - 3000, Belgium

Location

Uniklinikum Dresden

Dresden, 01307, Germany

Location

University Hospitals Bristol NHS Foundation Trust

Bristol, BS2 8ED, United Kingdom

Location

The Leeds Teaching Hospitals NHS Trust

Leeds, LS2 9LN, United Kingdom

Location

University College London Hospitals NHS Trust

London, NW1 2PG, United Kingdom

Location

MeSH Terms

Conditions

Myelodysplastic Syndromes; Leukemia, Myeloid, Acute

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms

Study Officials

• Emma Morris, MD

  University College London Hospitals

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 28, 2015
• First Posted: September 15, 2015
• Study Start: September 1, 2015
• Primary Completion: May 1, 2018
• Study Completion: May 1, 2018
• Last Updated: October 2, 2018

Record last verified: 2018-10

Locations

DE (1); GB (3); BE (2)